DESCRIPTION: This is a competitive renewal application for 5 years of funding to study the ontogeny and control of heme catabolism and bilirubin production in rats and newborn Rhesus monkeys, and to explore advanced and novel methods to measure carbon monoxide production in newborn infants as an indicator of risk for severe neonatal hyperbilirubinemia. As indicted in the abstract to the proposal, "a better understanding of the role of increased bilirubin production in all kinds of neonatal jaundice and the prevention of hemolytic jaundice has remained an overall objective of the investigator's program. As a corollary, a more targeted, preventive approach to jaundice in high producers of the pigment, who may not be able to eliminate bilirubin fast enough to avoid high levels in circulation and tissues, is still needed. Control of bilirubin production is a logical strategy but has unexplored consequences for the immature animal. Thus, an increasing emphasis on studies to explore further, the pivotal role of heme oxygenase (HO) in developmental heme metabolism, is necessary. For this purpose, the specific aims are to: 1) continue in vitro and in vivo characterization and assessment of the metalloporphyrin inhibitors of HO and identify them as potential modulators of neonatal bilirubin production based on potent HO inhibition, negligible photoroactivity, desirable tissue distribution and elimination characteristics, and minimal side effects; 2) study the ontogeny of HO through measurements of mRNA, protein, and activity of HO in the liver, spleen, and intestine of the developing rat, and determine the effect of metalloporphyrin administration on this ontogeny; and 3) continue development of CO-monitoring technology for bedside diagnosis of hemolysis or increased total bilirubin production from other causes. The long term clinical application of the research proposal is "to further develop a) non-invasive CO monitoring technology to identify neonates with high bilirubin production rates, and b) a safe and efficacious chemopreventive treatment regimen for infants at high risk for jaundice because of hemolysis." In support of the above specific aims, the investigators plan a wide- ranging series of studies designed to: 1) continue screening a variety of metalloporhyrins in vitro and in vivo for maximum efficacy and minimum side effects; 2) study the developmental ontogeny of the heme oxygenase enzyme system in various tissues from neonatal, suckling, and older rats, focusing on the intrinsic ontogeny of the heme oxygenase system and perturbations resulting from treatment with heme oxygenase inhibitors; and 3) further development and test instrumentation for non- invasive measurement of CO production in newborn infants, as an index of hemolysis or excess bilirubin production.